Depression and cardiovascular disease are the two largest public health problems in the Western world, and their appropriate prevention and treatment are enormous public health issues. Depression has been shown to predict increased morbidity and mortality among patients recovering from a myocardial infarction, independent of the severity of cardiac illness. The exact mechanisms linking depression and increased cardiovascular risk remain poorly understood. Increased serotonin (5-HT) mediated platelet reactivity has been postulated to be a major mechanism linking depression to acute coronary syndromes (ACS). Our own pilot work has shown that depressed mood is associated with enhanced 5-HT activated platelet aggregation in patients with ACS. The central hypothesis of this proposal is that 5-HT signaling is enhanced in platelets from ACS patients with depression. Three specific aims have been designed to systematically test this hypothesis: 1) Determine the effect of 5-HT on platelet activation by the measurement of 5-HT-augmented platelet aggregation and 5-HT- induced 1IIb23 expression, 2) Determine platelet uptake of 5-HT and 3) Determine 5-HT receptor density on platelets from ACS and stable CAD patients with varying severity of depression. To explore the possibility that alterations in 5-HT transporter function and 5-HT binding are linked to depression and ACS, patients will be genotyped for three specific 5-HT gene polymorphisms: a) 5-HT transporter polymorphism, 5-HTTLPR short and long, b) a newly recognized A for G single nucleotide polymorphism within the 5-HTTLPR insertion, and c) a T for C substitution at position 102 located in a non-coding DNA region of the 5-HT receptor. Platelet function and depression will be measured at baseline and at a one-month follow up. Examination of the relationship between 5-HT signaling, 5-HT polymorphisms, and adverse cardiac outcomes will be explored by assessing both major and minor adverse cardiac events that occur within a 12-month period after initial enrollment in both ACS and stable CAD patients. This will be conducted in a case controlled study recruiting subjects presenting with ACS and stable CAD whose symptoms of depression will be assessed using the Structured Clinical Interview for DSM-IV-R (SCID) to diagnose major depression and the Beck Depression Inventory (BDI) to provide a continuous measure of depressive symptoms. Comparisons will be made on platelets obtained from patients who have and do not have major depression by SCID criteria, and explored by categories of the BDI scores. A logical link between cardiovascular risk and depression is the platelet 5-HT signaling system given the central role that 5-HT plays in depression and the similarities between brain and platelet 5-HT receptors and transporters. Elucidation of the specific platelet activation pathways and their link to adverse cardiac events will provide information that is highly clinically relevant and important. Given the significant increased mortality in patients with ACS and depression, a better understanding of mechanisms leading to increased risk can lead to more targeted and aggressive therapy and potentially improved survival. PUBLIC HEALTH RELEVANCE: Major depression is an independent risk factor for cardiovascular mortality and morbidity. The exact mechanisms linking depression and increased cardiovascular risk remain poorly understood. Better understandings of mechanisms leading to increased risk will likely lead to more targeted and aggressive therapy and potentially improved survival.